Blood+ is set decades after the events of Blood: The Last Vampire. Under the care of her adoptive family, Saya Otonashi has been living the life of an anemic and amnesiac, but otherwise ordinary schoolgirl. Saya’s happy life is shattered when she is attacked by a chiroptera, and learns that she is the only one who can defeat them. Armed with her sword, Saya embarks on a journey with her family, allies and faithful servant, Haji, to rid the world of Chiroptera and rediscover her identity.

The series is initially set in present day (September 2005) Okinawa City (Koza), on Okinawa Island, near the US Kadena Air Base. In the course of the series, Saya visits locales across the world, while fighting enemy chiropterans and searching for her origins.